HSP90 and HSP70 Proteins Are Essential for Stabilization and Activation of WASF3 Metastasis-promoting Protein

Teng, Yong; Ngoka, Lambert C. M.; Mei, Yun; Lesoon, Leslieann; Cowell, John K.

doi:10.1074/jbc.m111.335000

Cited by 76 publications

(107 citation statements)

References 34 publications

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“…122 c-Abldependent phos phorylation of WAVE3, which is upregulated in advanced tumors and promotes metastasis, increased prostate cancer cell invasion, indicating a role for c-Abl in prostate cancer progression. 123 Moreover, activation of c-Abl by PDGF promoted prostate cancer cell survival by inducing expression of the antiapoptotic protein, MCL-1, via a p68/β-catenin signaling pathway (Fig. 1).…”

Section: Prostate Cancermentioning

confidence: 98%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

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Although c-Abl and Arg non-receptor tyrosine kinases are well known for driving leukemia development, their role in solid tumors has not been appreciated until recently. Accumulating evidence now indicates that c-Abl and/or Arg are activated in some solid tumor cell lines via unique mechanisms that do not involve gene mutation/translocation, and c-Abl/Arg activation promotes matrix degradation, invasion, proliferation, tumorigenesis, and/ or metastasis, depending on the tumor type. However, some data suggest that c-Abl also may suppress invasion, proliferation, and tumorigenesis in certain cell contexts. Thus, c-Abl/Arg may serve as molecular switches that suppress proliferation and invasion in response to some stimuli (e.g., ephrins) or when inactive/regulated, or as promote invasion and proliferation in response to other signals (e.g., activated growth factor receptors, loss of inhibitor expression), which induce sustained activation. Clearly, more data are required to determine the extent and prevalence of c-Abl/Arg activation in primary tumors and during progression, and additional animal studies are needed to substantiate in vitro findings. Furthermore, c-Abl/ Arg inhibitors have been used in numerous solid tumor clinical trials; however, none of these trials were restricted to patients whose tumors expressed highly activated c-Abl/Arg (targeted trial). Targeted trials are critical for determining whether c-Abl/Arg inhibitors can be effective treatment options for patients whose tumors are driven by c-Abl/Arg.

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Section: Prostate Cancermentioning

confidence: 98%

Activation of Abl Family Kinases in Solid Tumors

Ganguly

Plattner

2012

Genes & Cancer

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“…In contrast to normal cells, HSF1 and Hsp70 are highly overexpressed in tumor cells already under physiological conditions and thus contribute to tumor cell survival, migration, invasion and angiogenesis [1][2][3][4][5][6]. High HSF1 and Hsp70 levels are associated with poor prognosis, metastasis and therapy resistance [1,7,8].…”

Section: Introductionmentioning

confidence: 99%

Sensitizing tumor cells to radiation by targeting the heat shock response

et al. 2015

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Elevated levels of heat shock proteins (HSPs) contribute to tumor cell survival and mediate protection against radiation-induced cell death. Hsp90 inhibitors are promising radiosensitizers but also activate heat shock factor 1 (HSF1) and thereby induce the synthesis of cytoprotective Hsp70. In this study the heat shock response inhibitor NZ28 either alone or in combination with the Hsp90 inhibitor NVP-AUY922 was investigated for radiosensitizing effects, alterations in cell cycle distribution and effects on migratory/invasive capacity of radioresistant tumor cells. NZ28 reduced the constitutive and NVP-AUY922-induced Hsp70 expression by inhibition of the HSF1 activity and inhibited migration and invasion in human lung and breast tumor cells. Treatment of tumor cells with NZ28 significantly increased their radiation response. One possible mechanism might be a decrease of the radioresistant S-phase. When combined with the Hsp90 inhibitor NVP-AUY922 the concentration of NZ28 could be significantly reduced (1/10th-1/20th) to achieve the same radiosensitization. Our results demonstrate that a dual targeting of Hsp70 and Hsp90 with NZ28 and NVP-AUY922 potentiates the radiation response of tumor cells that are otherwise resistant to ionizing radiation.

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“…A long list of HSP client proteins can be found in the literature [51,52]. In cancer cells, HSP70 and HSP90 have been found to be essential for WASF3 metastasis-promoting protein stability, which contributes to cancer cell migration and invasion [36]. HSP90 has also been found to directly bind to the ribosomal protein rpS3 to prevent it from degradation through a ubiquitin-proteasome pathway [53].…”

Section: Discussionmentioning

confidence: 99%

“…First, a benzylidene lactam compound, KNK437-the most widely-used heat shock response inhibitor [23,[36][37][38]]-was applied to our experiments. KNK437 prevents the development of thermotolerance by inhibiting the up-regulation of various HSPs at the transcriptional level [39].…”

Section: Ie2-expressing Recombinant Virus Transduction Stimulates Hspmentioning

confidence: 99%

Baculovirus IE2 stimulates the expression of heat shock proteins in insect and mammalian cells to facilitate its proper functioning

Chao¹

2016

2016 International Congress of Entomology

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Baculoviruses have gained popularity as pest control agents and for protein production in insect systems. These viruses are also becoming popular for gene expression, tissue engineering and gene therapy in mammalian systems. Baculovirus infection triggers a heat shock response, and this response is crucial for its successful infection of host insect cells. However, the viral protein(s) or factor(s) that trigger this response are not yet clear. Previously, we revealed that IE2-an early gene product of the baculovirus-could form unique nuclear bodies for the strong trans-activation of various promoters in mammalian cells. Here, we purified IE2 nuclear bodies from Vero E6 cells and investigated the associated proteins by using mass spectrometry. Heat shock proteins (HSPs) were found to be one of the major IE2-associated proteins. Our experiments show that HSPs are greatly induced by IE2 and are crucial for the trans-activation function of IE2. Interestingly, blocking both heat shock protein expression and the proteasome pathway preserved the IE2 protein and its nuclear body structure, and revived its function. These observations reveal that HSPs do not function directly to assist the formation of the nuclear body structure, but may rather protect IE2 from proteasome degradation. Aside from functional studies in mammalian cells, we also show that HSPs were stimulated and required to determine IE2 protein levels, in insect cells infected with baculovirus. Upon inhibiting the expression of heat shock proteins, baculovirus IE2 was substantially suppressed, resulting in a significantly suppressed viral titer. Thus, we demonstrate a unique feature in that IE2 can function in both insect and nonhost mammalian cells to stimulate HSPs, which may be associated with IE2 stabilization and lead to the protection of the its strong gene activation function in mammalian cells. On the other hand, during viral infection in insect cells, IE2 could also strongly stimulate HSPs and ultimately affect viral replication.

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HSP90 and HSP70 Proteins Are Essential for Stabilization and Activation of WASF3 Metastasis-promoting Protein

Cited by 76 publications

References 34 publications

Activation of Abl Family Kinases in Solid Tumors

Activation of Abl Family Kinases in Solid Tumors

Sensitizing tumor cells to radiation by targeting the heat shock response

Baculovirus IE2 stimulates the expression of heat shock proteins in insect and mammalian cells to facilitate its proper functioning

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